Epicardial coronary artery spasm is of pathophysiological importance in myocardial infarction, angina pectoris, and Prinzmetal's angina; however, the mechanisms which cause abnormal contractions of coronary smooth muscle are unknown. The central hypothesis of this proposal is that vascular damage and disease results in altered physiological and pharmacological control of coronary vascular smooth muscle, and that these alterations result in coronary vasospasm. A cardinal feature of coronary vasospasm is its episodic nature; for this reason acute discharges of 1) vasoactive substances from platelets aggregating at sites of endothelium damage and/or 2) vasoconstrictor transmitters from autonomic nerves have been implicated as mediators of spasm. In vitro studies done on canine and porcine coronary arteries in this laboratory have 1) demonstrated the smooth muscle relaxing influence of norepinephrine released by adrenergic nerves and the contractile influence of acetylcholine released by cholinergic nerves, 2) determined the reactivity of coronary arteries to platelet-released substances including 5-hydroxytryptamine and adenine nucleotides, and 3) discovered that platelets aggregating at sites of coronary artery damage or disease may deleteriously alter the dilator funciton of the nerves. In vitro and in vivo studies will pursue the hypothesis that 5-hydroxytryptamine released by paltelets may be accumulated by, and released as a false neurotransmitter from, coronary adrenergic nerves converting them to constrictor nerves; preliminary studies have shown that twenty-four hours following balloon damage to the endothelium resulting in platelet aggregation in vivo, adrenergic nerve stimulation causes serotonergic coronary contractions. Response to autonomic nerve stimulation will be determined in rings of coronary artery in vitro in each of three models of arterial damage and disease: 1) during in vitro exposure to platelet released vasoactive substances, 2) following balloon denudation of endothelium in vivo, and 3) six weeks following endothelium damage of cholesterol fed animals which results in intimal hyperplasia similar to that seen in human coronary atherosclerosis. Correlated with functional studies of coronary arteries will be 1) pharmacological characterization of autonomic and serotonergic receptors, 2) biochemical determinations of the quantity and metabolism of neurotransmitters, and 3) histological studies to detect changes in the density and distribution of autonomic nerves in the coronary arterial wall.